The Interactive Impact of Cocaine and Schizophrenia on Prefrontal Function

描述(申请人提供)：精神分裂症和可卡因依赖导致残疾，部分是通过损害执行认知功能。此外，精神分裂症患者患可卡因依赖的风险增加。当戒除可卡因时，共病患者的症状有所减轻，但执行认知功能比其他精神分裂症患者差。这一建议探讨了精神分裂症和可卡因依赖的交互认知神经科学。它建立在我们已故同事Patricia Goldman-Rakic的工作基础上，他在猴子身上表明，工作记忆(WM)维持阶段的前额叶皮质(PFC)活动取决于多巴胺D1受体功能，而WM反应选择阶段的PFC活动取决于D2受体功能。我们建议使用功能磁共振成像(FMRI)来比较四组受试者中与WM和皮质功能连接性相关的PFC活动：健康人、戒断性可卡因依赖者、精神分裂症患者和戒除性可卡因依赖型精神分裂症患者。我们的初步数据表明，在西医的维持期，共病组的PFC活性缺陷比任何一个单独诊断组都要大，这可能与PFC D1受体功能的缺陷有关。然而，共病组表现出比单一诊断组或健康受试者更大的反应期活动，这表明可卡因使用相关的PFC D2受体功能增强。通过强调与精神分裂症和可卡因依赖的相互作用有关的认知功能障碍的新的电路适应，这一应用可能为PFC机制提供新的线索，这些机制导致与精神分裂症、可卡因依赖及其共病有关的较差的认知结果。公共卫生相关性这个项目可能帮助我们了解精神分裂症和可卡因滥用如何影响前额叶功能，这些因素在精神分裂症和可卡因依赖的共病患者中如何相互作用。这些知识可能会帮助我们为那些同时患有精神分裂症和可卡因依赖的人开发更好的治疗方法。

DESCRIPTION (provided by applicant): Schizophrenia and cocaine dependence produce disability, in part, by impairing executive cognitive function. Also, schizophrenic patients are at increased risk for developing cocaine dependence. When abstinent from cocaine, comorbid patients show reduced symptoms, but poorer executive cognitive function than other schizophrenic patients. This proposal probes the interactive cognitive neuroscience of schizophrenia and cocaine dependence. It builds on the work of our late colleague, Patricia Goldman-Rakic, who showed in monkeys that prefrontal cortex (PFC) activity during the maintenance phase of working memory (WM) was dependent upon dopamine D1 receptor function, while PFC activity during the response selection phase of WM was dependent upon D2 receptor function. We propose to use functional magnetic resonance imaging (fMRI) to compare PFC activity associated with WM and cortical functional connectivity in four groups of subjects: healthy individuals, abstinent cocaine dependent individuals, schizophrenia patients, and abstinent cocaine dependent schizophrenic patients. Our pilot data suggest that the comorbid group shows greater PFC activity deficits in the maintenance phase of WM than either single diagnosis group, perhaps related to greater deficits in PFC D1 receptor function. However, the comorbid group shows greater response phase activity than either single diagnosis group or healthy subjects, suggestive of a cocaine use-related enhancement of PFC D2 receptor function. By highlighting novel circuit adaptations that contribute to cognitive dysfunction associated with the interplay of schizophrenia and cocaine dependence, this application may shed new light on PFC mechanisms that contribute to poorer cognitive outcomes associated with schizophrenia, cocaine dependence, and their comorbidity. PUBLIC HEALTH RELEVANCE This project may help us to understand how schizophrenia and cocaine abuse affect prefrontal function how these factors interact in those who are co-morbid for schizophrenia and cocaine dependence. Such knowledge may help us to develop better treatments for those who are comorbid for schizophrenia and cocaine dependence.